Immunomodulation for intestinal transplantation by allograft irradiation, adjunct donor bone marrow infusion, or both.
Murase, N and Ye, Q and Nalesnik, MA and Demetris, AJ and Abu-Elmagd, K and Reyes, J and Ichikawa, N and Okuda, T and Fung, JJ and Starzl, TE
(2000)
Immunomodulation for intestinal transplantation by allograft irradiation, adjunct donor bone marrow infusion, or both.
Transplantation, 70 (11).
1632 - 1641.
ISSN 0041-1337
Abstract
BACKGROUND: The passenger leukocytes in the intestine have a lineage profile that predisposes to graft-versus-host disease (GVHD) in some animal models and have inferior tolerogenic qualities compared with the leukocytes in the liver, other solid organs, and bone marrow. Elimination by ex vivo irradiation of mature lymphoid elements from the bowel allografts is known to eliminate the GVHD risk. We hypothesized that infusion of donor bone marrow cells (BMC) in recipients of irradiated intestine would improve tolerogenesis without increasing the risk of GVHD. METHODS: Orthotopic small intestine transplantation was performed with the GVHD-prone Lewis (LEW)-to-Brown Norway (BN) combination and the reverse GVHD-resistant BN-to-LEW model under a short course of tacrolimus treatment (1 mg/kg/day, days 0-13, 20, 27). Grafts were irradiated ex vivo, using a 137Cs source. In selected experimental groups, donor BMC (2.5 x 10(8)) were infused on the day of small intestine transplantation. RESULTS: The unmodified LEW intestine remained intact, whether transplanted alone or with adjunct donor BMC infusion, but all of the BN recipients died of GVHD after approximately 2 months. Intestinal graft irradiation (10 Gy) effectively prevented the GVHD and prolonged survival to 92.5 days, but all of the BN recipients died with chronic rejection of the LEW grafts, which was prevented by infusion of adjunct donor BMC without causing GVHD. In the GVHD-resistant reverse strain direction (BN-->LEW), all intestinal recipients treated for 27 days with tacrolimus survived > or =150 days without regard for graft irradiation or adjunct BMC, but chronic rejection was severe in the irradiated intestine, moderate in the unaltered graft, and least in the irradiated intestine transplanted with adjunct BMC. Mild arteritis in the 150 day allografts of both strain combinations (i.e., LEW--> BN and BN-->LEW) may have been irradiation associated, but this was prevented when weekly doses of tacrolimus were continued for the duration of the experiment rather than being stopped at 27 days. CONCLUSIONS: Recipients are protected from GVHD by irradiating intestinal allografts, but the resulting leukocyte depletion leads to chronic rejection of the transplanted bowel. The chronic rejection is prevented with adjunct donor BMC without causing GVHD. Although application of the strategy may be limited by the possibility of radiation injury, the results are consistent with the paradigm that we have proposed to explain organ-induced graft acceptance, tolerance, and chronic rejection.
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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Murase, N | | | | | Ye, Q | | | | | Nalesnik, MA | | | | | Demetris, AJ | | | | | Abu-Elmagd, K | | | | | Reyes, J | | | | | Ichikawa, N | | | | | Okuda, T | | | | | Fung, JJ | | | | | Starzl, TE | tes11@pitt.edu | TES11 | |
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| Centers: |
Other Centers, Institutes, Offices, or Units > Thomas E. Starzl Transplantation Institute |
| Date: |
15 December 2000 |
| Date Type: |
Publication |
| Journal or Publication Title: |
Transplantation |
| Volume: |
70 |
| Number: |
11 |
| Page Range: |
1632 - 1641 |
| DOI or Unique Handle: |
10.1097/00007890-200012150-00016 |
| Institution: |
University of Pittsburgh |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Animals, Dose-Response Relationship, Radiation, Graft Survival, Graft vs Host Disease, Intestine, Small, Leukocytes, Lymph Nodes, Male, Mesentery, Rats, Rats, Inbred BN, Rats, Inbred Lew, Transplantation Chimera, Transplantation, Homologous |
| ISSN: |
0041-1337 |
| Funders: |
NIDDK NIH HHS (R01 DK54232), NIDDK NIH HHS (R01 DK029961-19), NIAID NIH HHS (R01 AI038899), NIDDK NIH HHS (R01 DK054232), NIDDK NIH HHS (DK 29961) |
| Other ID: |
uls-drl:31735062120393, Starzl CV No. 2129 |
| Date Deposited: |
08 Apr 2010 17:36 |
| Last Modified: |
16 Jul 2019 14:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/5515 |
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